Search

Tetraphenylethene (TPE) shows a significant increase of fluorescence intensity when the rotational freedom of its phenyl groups is restricted. This special property allows the use of TPE in sensor applications, which have been previously described for the liquid phase only. However, some applications utilising arrays require the immobilisation of TPE dyes on solid surfaces. In this work, we synthesised and investigated the fluorescence behaviour of TPE derivatives on silica particles and quartz slides and suggest ways to employ the dye's properties in solid phase biosensor applications.

Palladium cyclization cascades represent an elegant way to access complex polycyclic scaffolds in a minimum amount of steps. Herein we provide a complete account on two new methodologies including these kind of cascades, each leading to two types of attractive compounds, cyclooctatrienes and [4.6.4.6]fenestradienes. The reader will first discover a strategy requiring three steps starting from alkenyl bromides, based on a first 4- exo -dig carbopalladation/Sonogashira coupling tandem reaction, and a subsequent P-2 Ni induced semi-hydrogenation. This leads to a first generation of cyclooctatrienes and [4.6.4.6]fenestradienes. Next, the second approach will be presented, in which the second generation of these compounds is accessed in a one-pot reaction including five steps, starting from the same alkenyl bromide compounds. These methods are appealing in terms of atom economy, the use of easy to handle conditions as well as the variability of its scope.

Malaria remains a significant infectious disease with even artemisinin-based therapies now facing resistance in the field. Development of new therapies is urgently needed, either by finding new compounds with unique modes of action, or by reversing resistance towards known drugs with 'chemosensitizers' or 'chemoreversal' agents (CRA). Concerning the latter, we have focused on the resistance mechanisms developed against chloroquine (CQ). We have synthesized a series of compounds related to previously identified CRAs, and found promising novel compounds. These compounds show encouraging results in a coumarin labeled chloroquine uptake assay, exhibiting a dose response in resensitising parasites to the antimalarial effects of chloroquine. Selected compounds show consistent potency across a panel of chloroquine and artemisinin sensitive and resistant parasites, and a wide therapeutic window. This data supports further study of CRAs in the treatment of malaria and, ultimately, their use in chloroquine-based combination therapies.

only one or two bonds are formed at a time, but by triggering a cascade of reactions many bonds can be formed in one operation and thus simple starting materials can be efficiently converted into highly sophisticated complex structures. Achieving complexity with such brevity is indeed a key characteristic of the ideal and green synthesis. [2] Toward these ends, we have focused our attention on developing facile routes to unusual scaffolds to prepare structurally diverse materials of potential theoretical and biological value. [3] Fenestranes have been examined by different research groups from both a theoretical and a synthetic perspective because of their unique structure and occurrence in nature, and their unexplored potential as molecular scaffolds, probes, and materials. [4] Several syntheses of fenestranes have been reported and since the appearance of the earliest contributions in this field, access to these compounds has improved in terms of the number of steps required and overall yield. [5] Intramolecular arene–olefin photo-cycloadditions, [6] photoinduced [2+2] cycloadditions, [7] transition-metal-induced cyclizations, [8] and cascade cyclizations [9] are some of the powerful methods that have been used to generate this class of compounds. A new approach to the fenestranes was recently demonstrated by our group. [10] Although, fenestradienes 4 were obtained in excellent yields, the method required the use of tin compounds, a sensitive nickel(0) catalyst, and hydrogen, and the intermediate trienyne species 3 was prone to polymerization if not handled with special care (Scheme 1). We herein report a one-step procedure that overcomes these problems and provides facile access to substituted fenestradienes 2 directly from alkenyl bromides 1 (Scheme 1). Our approach was inspired by a method developed by Trost et al. [11] for the selective synthesis of head-to-tail enynes in the presence of Pd(OAc)2 and tris(2,6-dimethoxyphenyl)phosphine (TDMPP), and a similar method developed by Gevorgyan and Rubina for the palladium-catalyzed headto-head dimerization of aryl acetylenes (Scheme 2). [12] The high regio- and stereoselectivities of these reactions were attributed to the strong steric influence of the ester group R 2 and specific agostic interactions between the ortho proton of the aromatic ring and the palladium center, respectively.

Herein we describe new accesses to dienynes and trienynes using new cascade reactions: 4-exo-dig cyclocarbopalladation followed by a Suzuki–Miyaura or Sonogashira cross-coupling.

Resistance to antimalarial therapies, including artemisinin, has emerged as a significant challenge. Reversal of acquired resistance can be achieved using agents that resensitize resistant parasites to a previously efficacious therapy. Building on our initial work describing novel chemoreversal agents (CRAs) that resensitize resistant parasites to chloroquine (CQ), we herein report new hybrid single agents as an innovative strategy in the battle against resistant malaria. Synthetically linking a CRA scaffold to chloroquine produces hybrid compounds with restored potency toward a range of resistant malaria parasites. A preferred compound, compound 35, showed broad activity and good potency against seven strains resistant to chloroquine and artemisinin. Assessment of aqueous solubility, membrane permeability, and in vitro toxicity in a hepatocyte line and a cardiomyocyte line indicates that compound 35 has a good therapeutic window and favorable drug-like properties. This study provides initial support for CQ-CRA hybrid compounds as a potential treatment for resistant malaria.

The scaffold of fenestranes is quite unique, as it contains four condensed cycles and a distorted tetracoordinated central carbon atom with bond angles greater than the regular 109°28". In this Minireview, a detailed overview on the developments regarding this compound class, including their synthesis, is given for the time period since 2006. In the past years, natural products that belong to the class of heterofenestranes have been isolated and their syntheses will also be discussed.

Palladium cyclization cascades represent an elegant way to access complex polycyclic scaffolds in a minimum amount of steps. Herein we provide a complete account on two new methodologies including these kind of cascades, each leading to two types of attractive compounds, cyclooctatrienes and [4.6.4.6]fenestradienes. The reader will first discover a strategy requiring three steps starting from alkenyl bromides, based on a first 4- exo -dig carbopalladation/Sonogashira coupling tandem reaction, and a subsequent P-2 Ni induced semi-hydrogenation. This leads to a first generation of cyclooctatrienes and [4.6.4.6]fenestradienes. Next, the second approach will be presented, in which the second generation of these compounds is accessed in a one-pot reaction including five steps, starting from the same alkenyl bromide compounds. These methods are appealing in terms of atom economy, the use of easy to handle conditions as well as the variability of its scope.

The scaffold of fenestranes is quite unique, as it contains four condensed cycles and a distorted tetracoordinated central carbon atom with bond angles greater than the regular 109°28". In this Minireview, a detailed overview on the developments regarding this compound class, including their synthesis, is given for the time period since 2006. In the past years, natural products that belong to the class of heterofenestranes have been isolated and their syntheses will also be discussed.

Due to the widespread prevalence of resistant parasites, chloroquine (CQ) was removed from front-line antimalarial chemotherapy in the 1990s despite its initial promise of disease eradication. Since then, resistance-conferring mutations have been identified in transporters such as the PfCRT, that allow for the efflux of CQ from its primary site of action, the parasite digestive vacuole.Chemosensitizing/chemoreversing compounds interfere with the function of these transporters thereby sensitizing parasites to CQ once again. However, compounds identified thus far have disappointing in vivo efficacy and screening for alternative candidates is required to revive this strategy. In this study, we propose a simple and direct means to rapidly screen for such compounds using a fluorescent-tagged CQ molecule. When this screen was applied to a small library, seven novel chemosensitizers (octoclothepin, methiothepin, metergoline, loperamide, chlorprothixene, L-703,606 and mibefradil) were quickly elucidated, including two which showed greater potency than the classical chemosensitizers verapamil and desipramine.

A series of quartz surfaces were modified with a series of crosslinkers and functional groups in order to obtain an azide-terminated monolayer, which was then used to immobilize pyrene onto the surface via alkyne-azide "click" chemistry. During the course of the immobilization, different ratios of tert-butyl diphenyl chlorosilane were used to control the distribution and hence the photophysical properties of the pyrene on the surface. The preparative surface reactions and photophysical properties were investigated with contact angle, X-ray photoelectron spectroscopy, UV-visible absorption and emission spectroscopy. High surface coverage was achieved of just under 1molecule per nm2. At this coverage all emission from the pyrene was in the form of excimer emission. Excimer emission dominated at all surface coverages greater than 0.45 molecules per nm2. Below this coverage the monomer emission could also be observed. The conclusions that can be drawn are important for understanding the interactions of neighboring molecules in molecular monolayers. Our results suggest that at high surface coverage a substantial number of the pyrene molecules are already close enough to their neighbors that pairs of them can be directly excited to form excimer with no requirement for diffusion. This can be stated because the long wavelength end of the pyrene absorption and excitation spectra show a broad tail that is assigned to a charge transfer band resulting from an electron being directly transferred from a ground state pyrene to a neighboring pyrene molecule. Furthermore, absorption spectra shifts also indicate that the pyrene molecules undergo some interactions on the surface when they are closely packed.

Herein we describe new accesses to dienynes and trienynes using new cascade reactions: 4-exo-dig cyclocarbopalladation followed by a Suzuki–Miyaura or Sonogashira cross-coupling.

International audience